An overview of gene therapy in sickle cell disease with a focus on the risk-benefit ratio observed in clinical trials and practice.
Ifeyinwa Osunkwo, MD: That’s a great segue into the next section: the role of curative therapy, including gene therapy, in the management of sickle cell disease. One treatment option we didn’t get to is transfusion therapy, which is an amazing intervention to take care of acute complications—chest, stroke, sequestration episodes, preoperatively multiorgan failure. But it’s also given chronically to prevent recurrent strokes or when you have your first stroke. However, there are curative therapy options for sickle cell disease, and it’s important that people are aware. As Dr Shah said, we notify people that these are the options we have. Multimodal therapy, as Dr Smith and Dr Desai mentioned, is going to be the way to go. Some of that will play out based on your insurance coverage and access, but 1 drug isn’t going to fix it all for sickle cell disease. Is there an option for some intervention to completely fix it all?
Let’s talk about gene therapy. Starting with Dr Shah, what’s the role of gene therapy? I want to hear your perspective on gene therapy. Who should get it? Who has gotten it? How does it play out in terms of your clinical practice? Once that’s done, I want to go to Dr Desai about the risk-benefit ratio of gene therapy. Dr Shah, let’s start with you. Gene therapy, yea or nay?
Nirmish Ramesh Shah, MD: It’s too early for me to say yea. I can’t say yes for sure. What I can say is I’m optimistic. I’m glad Dr Desai will go through all the risks and things to consider because there are a lot, and we must put it in perspective. Let me start with the gene therapy. Why is it different from standard bone marrow transplant? The interesting part and the reason there’s optimism is that this is an autologous transplant; we’re taking the patient’s own stem cells from their marrow. We’re manipulating it. We’re changing the gene so they don’t have sickle cell. What they’re doing is inserting genes, or changing the genes, so they make more fetal hemoglobin targeting that 40% range, and then patients don’t have symptoms or complications from sickle cell. The cells aren’t sickling, and the results are pretty good.
Across the board, if you look at what’s out there, patients are not having pain. Their hemoglobin is pretty much normalizing. Their fetal hemoglobin is on the 40% to 45% range. I don’t think we’re arguing that it’s an issue, and the patients are not rejecting it because it’s their own marrow. They don’t have graft-vs-host disease because it’s their own marrow, so they don’t need immunosuppressive, which makes me very optimistic about what this can do. I prefer the doctor to give specifics, but how comfortable am I with the potential risk of doing this? I have to give busulfan-based conditioning, which is the chemotherapy. I have to clean out the marrow to make room for the new and improved marrow, and cleaning out the marrow with chemotherapy has risks.
That brings me to this moment. I only consider the most severe patients, who don’t have a match sibling donor. If I was to give you a type of patient, a patient who’s had recurrent strokes, has iron overload, I would rather them not get ongoing transfusions if possible. They have a lot of alloy antibodies, so I can’t even do exchange transfusions. The most severe may be candidates for gene therapy. If we can work out some of the considerations of what the risk is—I don’t know that number. Is it 2%, 3%, 5%? What’s the risk? Once I know that, I could probably give you a better idea of exactly what patients will be right and how many of my patients I would give this to.
Ifeyinwa Osunkwo, MD: Dr Desai, what are those risks? What would you counsel your gene therapy candidate who is gung-ho and wants to get this done? They heard about CRISPR-Cas9, and they want them to fix their sickle cell disease.
Payal Desai, MD: Not all gene therapy is equivalent, and there are several ways we do gene therapy. All of them carry their own adverse effects. We’re all shying away from calling it a potential cure because we don’t know. Let me be the Eeyore. Let me bring you down and talk about all the adverse effects, all the potential issues. I will preface this by saying that for that really complex patient, even in the adult world, they don’t have an option. The risks may be worth not knowing if you think that next acute chest episode might be it. They’ve had 10 episodes, and they’ve had more complications. Despite everything, they keep getting more complications. Even with the potential risk, this might be the right thing for them, and it’s not up to me to say how bad those risks should be. This should be their choice to make an informed decision.
What’s an informed decision? Dr Shah talked about this. There are potential adverse effects up front that, because sickle cell is a complex disease that might affect the marrow in ways we don’t know, particularly as patients get older. Is it because of the chemotherapy itself and the potential impact of long-term adverse effects? Some patients after gene therapy could go on to develop acute leukemia or myelodysplastic syndrome. For those 2 things, we’re trading out the sickle cell. People can live an event-free life with sickle cell, but for how long? Which patients are prone to this very serious life-ending complication? We need to identify those patients.
The other part has to be, is it the therapy itself? In terms of the fetal hemoglobin expression with the vectors they’ve used, that’s the 1 that has the most data, the vector site itself. Where it’s going in to fix the sickle cell has not been shown to be problematic. But when we look at the data from the American Society of Hematology [Annual Meeting], and we talk about CRISPR-Cas9—you snip and insert—there are sometimes chunks of DNA missing. What are the implications of that? What does that mean? Are the libraries appropriate for sickle cell in African Americans, who have seen most of this therapy? There are a lot of unknowns about how this is happening.
It’s promising if you look at that data. We all sat in the audience—I sat with some of you when they presented at the American Society of Hematology [Annual Meeting] a couple of years ago—when there were 30,000 people in the audience and we all used to sit together before COVID-19. All of us had this wash over us when we saw the cure data from gene therapy in sickle cell disease. We want it to be true, we want it to work, and we want it to be successful. But I’m the Nervous Nellie. I’m a little scared. What does that mean? Is it really a cure? How long does the cure last? What happens if there’s a complication? Do they have another infusion they do? Can they fix the problem if it causes MDS [myelodysplastic syndrome] or acute leukemia? Those are the unknowns.
I’m still very hopeful despite saying all this. We should go into it with open eyes and pick the patient who’s best suited for this therapy. Those risks are worth it, and I can’t quantitate what that looks like. To wake up without pain 1 day might be worth the risk for that patient. I can’t tell you where that inflection point is for that individual patient, and it’s their choice to make. But they should go into it knowing that it might impact their reproductive health. They may not be able to have babies after, and it might impact their potential marrow for long-term complications.
Transcript edited for clarity.